Enterovirus and Human Parechovirus Surveillance — United States, 2009–2013

Glen R. Abedi, MPH1; John T. Watson, MD1; Huong Pham, MPH1; W. Allan Nix1; M. Steven Oberste, PhD1; Susan I. Gerber, MD1

Enteroviruses (EVs) and human parechoviruses (HPeVs) are small, non-enveloped RNA viruses in the Picornaviridae family, which are known or suspected to cause a spectrum of clinical manifestations in humans. Although most infected persons are asymptomatic, mild presentations can include respiratory infections, herpangina, and hand, foot, and mouth disease. Among the more severe syndromes associated with EV and HPeV infection are acute flaccid paralysis, meningitis, encephalitis, myocarditis, and sepsis. Neonates and infants are at higher risk for infection and for severe clinical outcomes than older children or adults (1–3). As of August 2015, a total of 16 HPeV types and 118 EV types (within four EV species known to infect humans: A, B, C, and D) had been identified, and the spectrum of illness caused differed among virus types (4). To describe trends in EV and HPeV circulating in the United States during 2009–2013, CDC summarized detections reported through two surveillance systems. The most commonly reported types of EV and HPeV during this period were coxsackievirus (CV) A6 and HPeV3. The large number of CVA6 detections likely reflected an increase in testing in response to an outbreak of severe hand, foot, and mouth disease in late 2011 and 2012 (5). Most HPeV3 detections originated from a single hospital that routinely tested for HPeV (6). Clinicians and public health practitioners should consider the EV and HPeV types recently circulating in the United States to inform diagnostic and surveillance activities. When EV and HPeV typing is performed, clinical and public health laboratories should routinely report their results to improve the reliability and generalizability of surveillance data.

The National Enterovirus Surveillance System (NESS) is a passive surveillance system that has been collecting laboratory data on types of EV and HPeV in the United States since the 1960s. Participating laboratories are asked to report detections monthly to NESS, as well as demographic (age, sex, and state) and laboratory (specimen collection date, specimen type, virus type) data. During 2009–2013, 17 laboratories from across the United States reported data to NESS, including the CDC Polio and Picornavirus Laboratory, the departments of health of 13 states and one city, one private reference laboratory, and one hospital laboratory. Detections were reported in 45 states and Puerto Rico (Figure 1). The U.S. Census Region most often named as the patients' location was the Midwest (40.0% of the 2,271 patients for whom state or territory was known), followed by the South (29.1%).

During 2009–2013, 2,724 specimens representing 2,532 patients tested for EV and HPeV were reported to NESS; the number of specimens submitted each year ranged from 392 in 2011 to 870 in 2012. The most commonly reported specimen types among those for which type was known (77.5% of 2,724 specimens) were cerebrospinal fluid (31.6%) and throat/nasopharyngeal swab (29.8%). Other frequently reported specimen types included stool/rectal swab (13.5%), tissue culture isolates (7.5%), and lesion swab/scraping (3.6%). Of the 1,763 patients for whom sex was reported, 56.2% were male. Age was reported for 1,763 patients. The age groups most widely represented were children aged <1 year (687 [39.0%]) and children aged 1–4 years (387 [22.0%]).

In 2,521 (99.6%) patients, only one virus type was identified, whereas two viruses were identified in specimens from 11 patients (0.4%). Similarly, most patients (2,402 [94.9%]) contributed only one specimen type, whereas the remainder (130 [5.1%]) contributed two or three. Virus type was reported for 1,819 (71.4%) of the 2,548 detected EVs and HPeVs (Table 1). The frequency with which individual types circulated from year to year varied considerably, with only echovirus 18 constituting at least 5% of reported annual detections in at least 4 of the 5 years. The most common types during the 5-year period were CVA6 (223 [12.3%]) and HPeV3 (223 [12.3%]) (Table 2). The majority (188 [84.3%]) of CVA6 detections during 2009–2013 occurred in 2012. NESS detected HPeV3 in 2010, 2012, and 2013, with 93.7% of patients presenting to a tertiary care pediatric hospital in Missouri that conducted routine testing for HPeV during the surveillance period (6). Type 2 vaccine-derived poliovirus was detected in one patient in 2009, as has been previously reported (7).

Similar to NESS, the National Respiratory and Enteric Virus Surveillance System (NREVSS) is a passive surveillance system that collects data on a number of viruses, including EVs but not HPeVs. Unlike NESS, NREVSS collects the total number of specimens tested as well as the number of positive tests and does not record virus type or patient-level data. It has been used to track on a weekly basis the proportion of positive tests for many viruses circulating in the United States, with "enterovirus" added as a separate category in 2007. In NREVSS, 93 laboratories in 37 states tested 273,559 enteric specimens for EVs by virus isolation (culture) during 2009–2013, and 86 laboratories in 31 states tested 152,446 specimens by reverse transcription–polymerase chain reaction; 2,358 (0.9%) and 18,006 (11.8%) were positive, respectively. In most years, the proportion of positive tests increased during March–June and decreased in November or December (Figure 2).

Discussion

The findings in this report are consistent with previous observations of changes over time in the virus types that predominate. Some types appear to circulate every year, whereas others circulate in a cyclical fashion with epidemic years followed by years with decreased activity (8).

Type-based enterovirus surveillance in the United States has five objectives: 1) to help public health practitioners determine long-term patterns of circulation for individual EVs; 2) to help interpret trends in enteroviral diseases (e.g., aseptic meningitis) by associating them with circulating types; 3) to assist with recognition of outbreaks associated with circulating types; 4) to help guide development of new diagnostic tests and therapies; and 5) to monitor poliovirus detections, thereby supplementing clinician-based poliomyelitis testing in the United States. Both paralytic poliomyelitis and nonparalytic poliovirus infections are nationally notifiable.

Frequency of reports to NESS is greatly influenced by increased awareness and demand for testing during outbreak periods. As a result, reports to NESS might be a closer reflection of outbreak-driven testing than of endemic circulation of the broader range of enteroviruses. During 2009–2013, the most common EV type reported to NESS was CVA6, of which an outbreak was first reported in the United States in 2010 and which was the predominant circulating type reported in 2012. Outbreaks of hand, foot, and mouth disease associated with CVA6 have been reported internationally since 2008 (9,10), including cases that occurred in multiple U.S. states during 2011–2012 (5). Other frequent reports to NESS include HPeV3, an important cause of neonatal sepsis.

The findings in this report are subject to at least five limitations. First, EV and HPeV infections other than poliovirus infections are not nationally notifiable in the United States. NESS is a passive system that relies on voluntary participation from laboratories, so findings are not necessarily representative of national or regional enterovirus activity. Second, the findings are limited by the lack of clinical information. Third, most typing is performed during the summer months; circulation during other parts of the year might be underrecognized. Fourth, although monthly NESS reporting is encouraged, not all participating laboratories submit timely data, which can delay the compilation of accurate data. Finally, the number of laboratories that continue to test for specific EV types has decreased over time as testing requests from clinicians become less frequent and as viral culture methods are discontinued. Only a handful of U.S. laboratories have the capacity to test for HPeV. Although molecular detection methods are gradually coming into wider use, some clinical laboratories use them only to determine the presence of EV and do not further test for type. HPeV are not detected by EV molecular methods. EV and HPeV molecular typing methods are carried out in a small number of state laboratories, but mostly remain the purview of large, specialized reference laboratories.

NESS allows monitoring of temporal patterns of EV and HPeV circulation based on voluntary laboratory reporting of isolates by type. NREVSS demonstrates EV activity over a wider geographic area and has more laboratory participation but does not provide information on type, demographic characteristics, or HPeV detections. The combined systems provide the best available data on EV circulation in the United States.

Understanding of currently circulating EV and HPeV types relies on voluntary reports to NESS from public health and clinical laboratories. The long-term viability of NESS depends on 1) maintaining and modernizing the capacity to identify and type EVs and HPeVs among public health and clinical laboratories, 2) continued regular reporting by currently participating laboratories, and 3) increasing the number of participating laboratories.

1Division of Viral Diseases, National Center for Immunization and Respiratory Disease, CDC.

Corresponding author: Glen Abedi, gabedi@cdc.gov, 404-639-5979.

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